Direct Ink Writing (DIW) 3D Printing for Fabricating Flexible Microfluidic Devices

Three-dimensional (3D) printing is becoming a new gold standard for the fabrication of microfluidic devices. Stereolithography (SL) printing has been increasingly used to fabricate fluidic channels albeit with restrictions in attainable channel dimensions, appliable resins, integration with functional components and materials. This paper discusses our recent progress in the fabrication of 3D-printed microchannels based on direct ink writing (DIW) 3D printing. DIW 3D printing allows patterning liquid precursors, including room-temperature-vulcanizing (RTV) silicone and addition-curing two-part silicone, on a variety of substrates. Direct writing of silicone elastomers has enabled fabricating channels on acrylic plates and elastomeric sheets. To highlight the advantage of DIW-fabricated fluidic devices, the fabrication of the ultra-deformable microfluidic electronic device is discussed. Overall, DIW 3D printing offers new opportunities for the automated fabrication of advanced microfluidic devices.</p

Highly-customizable 3D-printed peristaltic pump kit

Commercially available peristaltic pumps for microfluidics are usually bulky, expensive, and not customizable. Herein, we developed a cost-effective kit to build a micro-peristaltic pump (~ 50 USD) consisting of 3D-printed and off-the-shelf components. We demonstrated fabricating two variants of pumps with different sizes and operating flowrates using the developed kit. The assembled pumps offered a flowrate of 0.02 ~ 727.3 μL/min, and the smallest pump assembled with this kit was 20 × 50 × 28 mm. This kit was designed with modular components (i.e., each component followed a standardized unit) to achieve (1) customizability (users can easily reconfigure various components to comply with their experiments), (2) forward compatibility (new parts with the standardized unit can be designed and easily interfaced to the current kit), and (3) easy replacement of the parts experiencing wear and tear. To demonstrate the forward compatibility, we developed a flowrate calibration tool that was readily interfaced with the developed pump system. The pumps exhibited good repeatability in flowrates and functioned inside a cell incubator (at 37 °C and 95 % humidity) for seven days without noticeable issues in the performance. This cost-effective, highly customizable pump kit should find use in lab-on-a-chip, organs-on-a-chip, and point-of-care microfluidic applications.</p

Freestanding, Multilayered and Biomimetic Vasculature-on-a-Chip Model by 3D-Printed Porous Mold

Anatomically and biologically relevant vascular models are critical to progress our understanding of cardiovascular diseases (CVDs) that can lead to effective therapeutics. Current vascular models either lack biomimetic vascular tissue structures or anatomically accurate architectures. In this work, we developed a technique to fabricate anatomical accurate vascular models (i.e., freestanding, branching, multilayered, perfusable, mechanically stretchable) with the option of customizing the bioink blend to improve compatibility with relevant cells and the mechanical properties.</p

3D food printing of fresh vegetables using food hydrocolloids for dysphagic patients

Three-dimensional food printing (3DFP) leads to advances in digital gastronomy by targeting consumers’ specific requirements for nutrition customization and visual appeal. Dysphagia, or difficulty swallowing, is prevalent in elderly people and patients suffering from debilitating illnesses. Dysphagic diets require textural modifications to render them soft and safe to swallow. Diets must be visually pleasing to enable a greater food uptake to prevent malnutrition in patients. 3DFP so far has mainly utilized freeze-dried vegetable powders for shaping 3D designs. Our work focuses on fresh and frozen vegetables having better nutritional profile and low costs. Three different categories of vegetables are identified based on the number of hydrocolloids required to render them printable. Garden pea, carrot and bok choy are chosen as representatives in each category, which requires no HC, one type of HC and two types of HCs, respectively. Food inks are prepared by the addition of HCs i.e. xanthan gum (XG), kappa carrageenan (KC) and locust bean gum (LBG) for texture modification. Rheological, textural, microstructural and syneresis properties of the inks are examined. International dysphagia diet standardisation initiative (IDDSI) tests are done to assess the potential of the inks for dysphagic diets. Optimized ink formulations display excellent 3D printability, minimal water seepage, and dense microstructures with minimal amount of HCs. Using fresh vegetables instead of freeze-dried foods serves the purpose of preserving flavour and nutrition like real food. This in turn may bring 3DFP closer to the hospital and nursing home kitchens.National Research Foundation (NRF)Accepted versionThis work was supported by National Additive Manufacturing Innovation Cluster Project ID 2019048 569 and the National Research foundation Singapore under its Medium-Sized Centre funding scheme

Biomimetic Vasculatures by 3D-Printed Porous Molds

Despite recent advances in biofabrication, recapitulating complex architectures of cell-laden vascular constructs remains challenging. To date, biofabricated vascular models have not yet realized four fundamental attributes of native vasculatures simultaneously: freestanding, branching, multilayered, and perfusable. In this work, a microfluidics-enabled molding technique combined with coaxial bioprinting to fabricate anatomically relevant, cell-laden vascular models consisting of hydrogels is developed. By using 3D porous molds of poly(ethylene glycol) diacrylate as casting templates that gradually release calcium ions as a crosslinking agent, freestanding, and perfusable vascular constructs of complex geometries are fabricated. The bioinks can be tailored to improve the compatibility with specific vascular cells and to tune the mechanical modulus mimicking native blood vessels. Crucially, the integration of relevant vascular cells (such as smooth muscle cells and endothelial cells) in a multilayer and biomimetic configuration is highlighted. It is also demonstrated that the fabricated freestanding vessels are amenable for testing percutaneous coronary interventions (i.e., drug-eluting balloons and stents) under physiological mechanical states such as stretching and bending. Overall, a versatile fabrication technique with multifaceted possibilities of generating biomimetic vascular models that can benefit future research in mechanistic understanding of cardiovascular diseases and the development of therapeutic interventions is introduced.</p

Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI) : a phase 3, placebo-controlled, randomised trial

Background: Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor. Methods: The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population). Findings: Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3·3 years (IQR 2·8–3·8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7·3%] of 5558 vs 480 [8·6%] of 5596; HR 0·85 [95% CI 0·74–0·97], p=0·013). The same effect was not observed in patients without PCI (p=0·76, p interaction=0·16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3·1%] with ticagrelor vs 183 (3·3%) with placebo; HR 0·96 [95% CI 0·78–1·18], p=0·68), as well as all-cause death (282 [5·1%] vs 323 [5·8%]; 0·88 [0·75–1·03], p=0·11). TIMI major bleeding occurred in 111 (2·0%) of 5536 patients receiving ticagrelor and 62 (1·1%) of 5564 patients receiving placebo (HR 2·03 [95% CI 1·48–2·76], p<0·0001), and fatal bleeding in 6 (0·1%) of 5536 patients with ticagrelor and 6 (0·1%) of 5564 with placebo (1·13 [0·36–3·50], p=0·83). Intracranial haemorrhage occurred in 33 (0·6%) and 31 (0·6%) patients (1·21 [0·74–1·97], p=0·45). Ticagrelor improved net clinical benefit: 519/5558 (9·3%) versus 617/5596 (11·0%), HR=0·85, 95% CI 0·75–0·95, p=0·005, in contrast to patients without PCI where it did not, p interaction=0·012. Benefit was present irrespective of time from most recent PCI. Interpretation: In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk